Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream or the lymphatic system. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissue. By degrading these proteins, cancer cells are able to breach the ECM and escape. When oral cancers metastasize, they commonly travel through the lymph system to the lymph nodes in the neck. The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors of which about a dozen are known.
Cancer researchers studying the conditions necessary for cancer metastasis have discovered that one of the critical events required is the growth of a new network of blood vessels, called tumor angiogenesis. Angiogenesis inhibitors have therefore been proposed in preventing the growth of metastases.
Whether or not a cancer is local or has spread to other locations affects treatment and survival. If the cancer spreads to other tissues and organs, it may decrease a patient's likelihood of survival. When cancer has metastasized, it may be treated with radiosurgery, chemotheraphy, chemotheraphy, radiation therapy, biological therapy, hormone therapy, surgery, laser immunotheraphy, or a combination of these. The choice of treatment generally depends on the type of primary cancer, the size and location of the metastasis, the patient's age and general health, and the types of treatments used previously. Unfortunately, current treatment options are rarely able to cure metastatic cancer.
Cancer of the prostate may metastasize to the bones and/or to the lungs. In a similar manner, colon cancer has the tendency to metastasize to the liver. Stomach cancer often metastasizes to the ovary in women, where it is then called a Krukenberg tumor. It is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics.
Prostate cancer is a significant cause of morbidity and mortality among men in the Western world. In advanced cases, the disease becomes refractory to conventional treatments and death of the patient typically results from sequelae related to metastasis to sites including the bone and lungs.
Adenocarcinoma of the prostate is one of the most common malignancies. It is estimated that there are 220,000 new cases of prostate cancer will be diagnosed in the United States in 2007, and that it will cause more than 30,000 deaths during the year. In fact, prostate adenocarcinoma is the second leading cause of cancer-related mortality among men in the United States.
With prostate cancer, as with all solid tumors, it is the metastatic encroachment of the tumor on other vital function that causes the demise of the patient. Approximately 10% of patients are diagnosed initially with metastatic disease. Ultimately, 30-40% of patients with this cancer will develop metastatic disease. Once metastasis occurs, the cancer follows a relentless progression.
Invasion is a prerequisite for migration of tumor cells in connective tissue stroma and basement membranes form the major physical barriers to the migration process. Invasion of the local extracellular matrix (ECM) by tumor cells thus can be marked as the first step in metastasis. The sequential biochemical mechanism first involves cell attachment to specific components of ECM followed by a progressive cascade of proteolytic dissolution. Prostate cancers which grow to a critical size exhibit extracapsular invasion and metastasize to specific anatomical sites apparently in response to stromal cell secretory proteins which are necessary for their growth and proliferation. Invasive migration of tumor cells within the prostate gland may occur as a function of chemokinesis along anatomical paths of least resistance which include the perineural duct. Further establishment of metastasis relies upon successful penetration of the circulatory or lymphatic system, and vessel extravasation at the secondary organ which for prostate cancer is frequently bone and/or lung tissue. Nearly all of these steps, including attachment, matrix degradation and migration, can be modeled experimentally in vitro by measuring invasion of a reconstituted basement membrane (RBM) barrier in response to fibroblast-conditioned medium (FCM) used as a chemo-attractant.
Individual molecules associated with prostate cancer have been studied for their utility as vaccine antigens. For example, prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and prostatic acid phosphatase (PAP) have all been identified as immunogenic. PAP, as a vaccine antigen, has been shown to induce Th1 immunity in patients and conferred moderate clinical improvement. Clinical trials showed that patients vaccinated with dendritic cells loaded with recombinant PAP/granulocyte-macrophage-colony-stimulating factor (GM-CSF) protein had moderation of PSA levels and prolonged survival. Some patients having hormone-refractory prostate cancer showed moderation of PSA levels following vaccination with dendritic cells pulsed with various antigens, including PSA and PSMA. While some clinical success has been achieved with these antigens, none have resulted in long-term survival of patients
Use of autologous whole cell vaccines have been examined for a variety of cancers, including melanoma, lung cancer, colon cancer, and renal tumors. Varying degrees of efficacy were reported.
A phase I clinical trial of irradiated GM-CSF-secreting autologous prostate tumor cell vaccine therapy reported that the vaccine was well tolerated by patients and induced both B-cell and T-cell immune responses against antigens associated with prostate cancer cells. However, those investigators concluded that, while promising, autologous vaccines for prostate cancer were limited by the low yield of cells recovered from tumor harvest, even after expansion in cell culture. Instead, investigators have focused on the use of preparations composed of irradiated allogeneic prostate cancer cells, these cultured cells having been engineered to secrete GM-CSF, or allogenic cells with a Bacillus adjuvant as a means for treatment of prostate cancer. One study reported that vaccination slowed the rise of PSA in 40% of vaccinated patients, and an increased average time to disease progression of 58 weeks, compared to historical experience of 29-30 weeks.
Despite these and other reports, a need continues to exist in the medical and clinical arts for more effective methods and compositions for inhibiting metastasis and the spread of cancer.